Reagent for organic synthesis and method of organic synthesis reaction with the reagent

ABSTRACT

A reagent for organic synthesis with which a chemical reaction can be conducted in a liquid phase and unnecessary compound(s) can be easily separated at low cost from the liquid phase after completion of the reaction. The reagent for organic synthesis reversibly changes from a liquid-phase state to a solid-phase state with changes in solution composition and/or solution temperature, and is for use in organic synthesis reactions. This reagent for organic syntheses facilitates process development. With the reagent, research on and development of, e.g., medicines through, e.g., compound library synthesis, etc. can be accelerated. It can hence contribute to technical innovations in the biochemical industry and chemical industry.

TECHNICAL FIELD

The present invention relates to a reagent for organic synthesis and amethod of organic synthesis reaction using this reagent, and in moredetail, it relates to a reagent for organic synthesis which is acompound which rapidly changes from a liquid phase state to a solidphase state due to a change in solution composition and/or solutiontemperature, which is provided as a compound acting as a reactionsubstrate or a catalyst in an organic synthesis reaction, or which isprovided as a compound which bonds to unreacted compounds or byproductsin an organic synthesis reaction, which can be easily removed from thereaction system after the reaction; and to a method of organic synthesisusing this reagent.

BACKGROUND ART

In chemical reaction processes, methods of separating as a solid aspecified component dissolved in a liquid are widely used. This isbecause, by solidifying (crystallizing) only the specified component,separation and/or purification after the reaction are simplified. Inparticular, recently, in successive multistage synthesis such ascompound library synthesis and the like used in the research anddevelopment of pharmaceuticals, after the completion of each reaction,by solidifying (crystallizing) the unnecessary compounds, the removal ofthe solidified (crystallized) substances becomes easy, and it ispossible to prevent the processes from becoming complicated.

The solidification (crystallization) of specified components dissolvedin a solution in this way is implemented by satisfying definedconditions in the relationship with chemical properties and physicalproperties of the compounds, and with the solvent.

However, the conditions for solidification crystallization), in manycases, must be found by experience based on trial and error. Especially,in successive multistage synthesis, because it is necessary to considerthe solidification (crystallization) conditions based on thecharacteristic properties of the compounds synthesized in each of thestages, process development is very expensive and time consuming.

In order to solve such problems, in the prior art, there was known ameans of using a chemically modified reagent on polystyrene or silica,and separating the liquid including the products, and the reagents, byfiltration after the reaction. With these reagents, it is possible toeasily separate unreacted compounds added in excess, byproducts, andcatalysts, in an organic synthesis reaction or the like, withoutcomplicated separation processes.

Further, Patent Document 1 discloses a method for practicing anucleophilic substitution reaction (Mitsunobu reaction) of an alcoholfor producing a desired product, including a step of reacting an alcoholand a nucleophilic reagent with an azodicarboxylate and a phosphine,wherein at least one of the azodicarboxylate and phosphine include atleast one fluorous tag (a retention group of a highly fluorinated alkylgroup or the like). Here, for example, fluorous solvents includingperfluorocarbon or the like, will be present as a third phase withoutmixing with organic solvents or water, and have the characteristic ofdissolving compounds having a fluorous tag. Because of this, by adding afluorous solvent to a uniform reaction phase, it is possible to easilyseparate a compound which must be separated from the product, and whichhas a fluorous tag.

Further, by using a fluorous carrier which selectively bonds to afluorous tag, it is possible to easily separate a compound having afluorous tag by solid-liquid extraction.

Patent Document 1: Japanese Publication No. 2005-508890 of PCTApplication.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

However, in the case of utilizing a reaction using a chemically modifiedreagent on polystyrene or silica, for the reagent carried on thepolystyrene or silica, the reaction point is only at the solid liquidinterface, thus the reactivity is often low. Further, there was theproblem that it was not possible to use this method in many synthesisreactions where a product is produced by the reaction from stericallyplural directions, two or more reagents, because the reaction wascarried out on a solid surface.

Further, in the method disclosed in Patent Document 1, in the case ofusing a fluorous solvent when separating a compound having a fluoroustag, there was the problem that the costs of the reaction could not bekept low because fluorous solvents are expensive. Further, in the caseof using a fluorous carrier in the separation of a compound having afluorous tag, in addition to using an expensive fluorinated silica gelor the like, the separation operation is complex and cannot be easilyused.

The present invention was made in view of the above problems, and hasthe objective of providing a reagent for organic synthesis and a methodof organic synthesis reaction using the reagent, whereby a chemicalreaction can be carried out in a liquid phase, and further, theseparation of the unnecessary compounds from the liquid phase after thecompletion of the reaction can be carried out easily and also at lowcost.

Means for Solving the Problems

The present inventors have carried out diligent research in order tosolve the above problems. As a result, they arrived at and completed thepresent invention, discovering that by using a reagent for organicsynthesis including an aromatic group having a specified hydrophobicgroup, and having a property of reversibly changing from a liquid phasestate to a solid phase state according to changes in the solutioncomposition and/or the solution temperature, it is possible to carry outthe separation of unnecessary compounds from the liquid phase after thecompletion of the reaction, easily and furthermore, at low cost.

Specifically, the present invention provides the following.

The first aspect of the invention provides a reagent for organicsynthesis which can be used for organic synthesis reactions, shown inthe below Chemical Formula (1), having a property of reversibly changingfrom a liquid phase state to a solid phase state according to changes insolution composition and/or solution temperature.

(In the formula, R₁ to R₅ may be the same or different, and representhydrogen, halogen, or alkyl group with a carbon number of 1 to 30 whichmay have a substituent group, alkoxyl group with a carbon number of 1 to30 which may have a substituent group, aryl group with a carbon numberof 1 to 30 which may have a substituent group, acyl group with a carbonnumber of 1 to 30 which may have a substituent group, thioalkyl groupwith a carbon number of 1 to 30 which may have a substituent group,dialkylamino group with a carbon number of 1 to 30 which may have asubstituent group, nitro group or amino group, and at least two of R₁ toR₅ are alkyl group with a carbon number of 18 to 30 which may have asubstituent group, alkoxyl group with a carbon number of 18 to 30 whichmay have a substituent group, acyl group with a carbon number of 18 to30 which may have a substituent group, thioalkyl group with a carbonnumber of 18 to 30 which may have a substituent group, or dialkylaminogroup with a carbon number of 18 to 30 which may have a substituentgroup. Further, in the formula, X represents a reagent active sitehaving one or more atoms selected from the group consisting of a carbonatom, oxygen atom, sulfur atom, and nitrogen atom.)

According to the reagent for organic synthesis according to the firstaspect, in addition to having a reagent active site having one or moreatoms selected from the group consisting of carbon, oxygen, sulfur, ornitrogen atoms, it also has, as substituent groups on the aromatic ring,at least two of: alkyl group with a carbon number of 18 to 30 which mayhave a substituent group, alkoxyl group with a carbon number of 18 to 30which may have a substituent group, acyl group with a carbon number of18 to 30 which may have a substituent group, a thioalkyl group with acarbon number of 18 to 30 which may have a substituent group, or adialkylamino group with a carbon number of 18 to 30 which may have asubstituent group. Because of this, the reagent for organic synthesiscan be dissolved uniformly with high concentration in many organicsolvents, and it can react with a high degree of reactivity with othercompounds in many organic solvents.

Further, the reagent for organic synthesis according to the first aspectcan also be used mainly as a nucleophilic scavenger, electrophilicscavenger, synthesis building block, reaction accelerator, condensationagent, or metal ligand. Namely, it can be used in a wide range ofapplications, as a reaction substance for unnecessary substances such asbyproducts, catalysts, and unreacted reaction substrate and the like, asa reaction substrate in an organic synthesis reaction, and as a catalystor reaction accelerator in an organic synthesis reaction, and inaddition, it has the property of reversibly changing from a liquid phasestate to a solid phase state according to changes in solutioncomposition and/or solution temperature, and thus can be easilyseparated from the reaction system by solidification after the reaction.

In this way, any compounds added to a reaction system, and byproductsgenerated in the reaction system, can be easily separated from thereaction system, or a specified reaction substrate or reactionaccelerator can be added to the reaction system as a compound which canbe easily separated later, and can be easily separated from the reactionsystem after the completion of the reaction.

Further, in a reaction using the reagent for organic synthesis of thefirst aspect, the organic synthesis reaction can be carried out at lowcost without using particularly expensive reagents.

Here, the “reagent for organic synthesis” indicates all reagents usedfor carrying out organic synthesis reactions, or processes after thereaction, and includes reaction substrates, reaction accelerators, andsynthesis building blocks, and the like. The reagent for organicsynthesis according to the present invention is not particularly limitedin terms of the amount used, and can be used in any case such as thecase of use in large industrial quantities, or the case of use in smallquantities for testing, research or the like. In the present invention,in particular, the compound has a structure such as that shown inChemical Formula (1).

Further, the “reagent for organic synthesis” of the present inventionhas a “hydrophobic carrier group” as a portion thereof. In the presentinvention, “hydrophobic carrier group” indicates, in the compound (I), asite having a hydrophobic group, and specifically, in the ChemicalFormula (1), indicates a portion excluding the reagent active portionwhich is X.

Further, “nucleophilic scavenger” indicates a compound which can bond toexcess electrophilic reagents remaining unreacted with other reactionsubstrate substances among electrophilic reagents used a chemicalreaction, and to compounds having electrophilicity which are produced asreaction byproducts, and further to unreacted reaction substrate.

The term “electrophilic scavenger” indicates a compound which can bondto excess nucleophilic reagents remaining unreacted with other reactionsubstrate substances among nucleophilic reagents used in a chemicalreaction, and to compounds having nucleophilicity which are generated asreaction byproducts, and further to unreacted reaction substrate.

The term “synthesis building block” indicates an intermediate providedfor the organic synthesis reaction of the desired compound in thepresent invention, and indicates a general term for a compound which canimpart an arbitrary reagent activity to a reaction substrate byintroducing a specified functional group via chemical bonding in anarbitrary reaction substrate.

The term “condensation agent” indicates a compound which acts toaccelerate a dehydration condensation reaction by accelerating theelimination of active hydrogen and hydroxyl groups from a reactionsubstrate in a dehydration condensation reaction such as an estersynthesis reaction, amide synthesis reaction, ether synthesis reactionor the like.

The term “metal ligand” indicates a compound having an atomic groupwhich can coordinate and bond to a metal ion added as a catalyst orreaction accelerator in an organic synthesis reaction.

Further, “reaction accelerator” indicates a compound which canaccelerate an organic synthesis reaction by addition to a reactionsystem, and for example, acids, bases, catalysts and the like can bementioned.

The second aspect of the invention provides a reagent for organicsynthesis according to the first aspect, characterized in that, inChemical Formula (1), X is a functional group shown by (A) to (M), or(A′) to (M′) below.

(In the formulas (A) to (M), Y is an ester bond, ether bond, amide bond,thioester bond, sulfide bond, urea bond, carbamate bond, or carbonatebond, or an alkylene group with a carbon number of 1 to 10 which mayhave such bonds. Further, in formulas (M) and (M′), m and n areindependently 0 or 1, Za is a chlorine atom or a bromine atom, Zb is ahydroxyl group, chlorine atom, or a bromine atom.)

Here, a “carbamate bond” is the chemical bond shown in Chemical Formula(N).

Further, a “carbonate bond” is the chemical bond shown in ChemicalFormula (O).

The reagent for organic synthesis of the second aspect can be used forthe following applications. Namely, in the case that among the compounds(1) indicated in the second aspect, X is reagent active site shown bythe Chemical Formula (A) to (C) or (A′) to (C′), because it has areaction center having nucleophilicity, such as a thiol group, aminogroup, or the like, it can be used as a nucleophilic scavenger.

Further, in the case that among the compounds (1) shown in the secondaspect, X is a reagent active site indicated by the Chemical Formulas(D) to (H), or (D′) to (H′), because it has a reaction center havingelectrophilicity, such as a carbonyl carbon atom, or the like, it can beused as an electrophilic scavenger. Further, also in the case that amongthe compounds (1), X is a reagent active site shown by the ChemicalFormulas (M), or (M′), because the carbon atom to which a hydroxyl groupis bonded, and the carbon atom to which to a halogen atom, not directlybonded to a benzene ring, is bonded have electrophilicity it can be usedas an electrophilic scavenger.

Moreover, in the case that among the compounds (I) indicated in thesecond aspect, X is a reagent active site shown by the Chemical Formulas(A) to (H), or (A′) to (H′), because structural changes for a compoundhaving arbitrary reagent activity are possible via a sulfide bond,thioester bond, amino bond, amide bond, carbamate bond, urea bond,carbonate bond, ether bond, or ester bond, it can also be used as asynthesis building block.

In the case that among the compounds (1) indicated in the second aspect,X is a reagent active site shown by the Chemical Formulas (I), (J), (I′)or (J′), because an amino group or the like shows strong basicity, itcan be used as a reaction accelerator as a strong base. Namely, thesecompounds, as strong bases, by capturing active hydrogen of one portionof the reaction substrate, can be used as reaction accelerators fornucleophilic reactions, deprotecting reactions, esterification reactionsof carboxylic acids, alkylation reactions of active methylenes,alkylation reactions of amines, alkylation reactions of phenols,alkylation reactions of thiols, and the like.

In the case that among the compounds (1) indicated in the second aspect,X is a reagent active site shown by the Chemical Formulas (K), or (K′),the unbonded electron pair of the phosphorous atom is donated to a metalatom, and in addition, an electron pair is back-donated from the metalatom to the π orbital of the tertiary phosphine. Because of this, thesecompounds can form strong coordination bonds with metal atoms.

Further, in the case that among the compounds (1) indicated in thesecond aspect, X is a reagent active site shown by the Chemical Formulas(K), (L), (K′), or (L′), because (K) or (K′) act in the same way astriphenylphosphine, and further, because (L) or (L′) act in the same wayas diethyl azodicarboxylate, these can be used as condensation agentsfor many condensation reactions publicly known as Mitsunobu reactions.

The third aspect of the invention provides a reagent for organicsynthesis according to the first or second aspect, wherein in theChemical Formula (1), R₂ and R₄ are a docosyloxy group (C₂₂H₄₅O—), andR₁, R₃ and R₅ are hydrogen.

Because the reagent for organic synthesis according to the third aspecthas two docosyloxy groups, it can be dissolved uniformly at highconcentration in many organic solvents, and it can react with a highdegree of reactivity with other compounds in many organic solvents.

The fourth aspect of the invention provides a reagent for organicsynthesis according to the third aspect, wherein in the Chemical Formula(1), the reagent active site X is a functional group shown by theformula (M) or (M′).

The reagent for organic synthesis according to the fourth aspect is,specifically, the compound shown by Chemical Formula (2a).

(In Formula (2a), m and n are independently 0 or 1, Za is a chlorineatom, or bromine atom, Zb is a hydroxyl group, chlorine atom, or bromineatom.)

Because the reagent for organic synthesis according to the fourth aspecthas a hydroxyl group, chlorine atom, or bromine atom, it can be used asan electrophilic scavenger. Further, because the reagent for organicsynthesis according to the fourth aspect has two docosyloxy groups, itcan be dissolved uniformly at high concentration in many organicsolvents, and it can react with a high degree of reactivity with othercompounds in many organic solvents.

The fifth aspect of the invention provides a reagent for organicsynthesis according to the first aspect, wherein in the Chemical Formula(1), the reagent active site X is a hydroxymethyl group, and R₂ and R₄are a docosyloxy group (C₂₂H₄₅O—), and R₁, R₃ and R₅ are hydrogen.

In other words, the invention according to the fifth aspect is a reagentfor organic synthesis shown by the following Chemical Formula (2) whichcan be used for organic synthesis,

Because the reagent for organic synthesis according to the fifth aspecthas a hydroxyl group, it can be used as an nucleophilic scavenger.Further, because the reagent for organic synthesis according to thefifth aspect has two docosyloxy groups, it can be dissolved uniformly athigh concentration in many organic solvents, and it can react with ahigh degree of reactivity with other compounds in many organic solvents.

The sixth aspect of the invention provides a method of organic synthesisreaction using the reagent for organic synthesis according to any one ofthe first to fifth aspects, comprising a reaction step of carrying out areaction wherein the reagent for organic synthesis is dissolved in areaction system where the reagent active site X of Chemical Formula (1)participates in the reaction, and after this, a separation step ofseparating the reagent for organic synthesis and the reacted reagent fororganic synthesis.

Taking note of the reagent for organic synthesis disclosed in the fifthaspect, the invention according to the sixth aspect is method of organicsynthesis reaction using the reagent for organic synthesis according tothe fifth aspect, comprising a reaction step of carrying out a reactionwhere the reagent for organic synthesis is dissolved in a reactionsystem where the hydroxyl group in Chemical Formula (2) participates inthe reaction, and after this, a separation step of separating thereagent for organic synthesis and the reacted reagent for organicsynthesis.

According to the method of organic synthesis reaction according to thesixth aspect, in the reaction step, it is possible to carry out achemical reaction for producing the desired compound, using the reagentfor organic synthesis according to any one of the first to fifthaspects. Further, because it is possible to separate, by the separationstep, byproducts having a hydrophobic carrier group of the reagent fororganic synthesis among the byproducts produced by the chemicalreaction, and the reagent for organic synthesis added to the reactionsystem in excess and remaining unreacted, it is possible to easily carryout a procedure of separating other compounds from the desired compound.

Further, in the reaction step of the method of organic synthesisreaction according to the sixth aspect, it is also possible to add areagent for organic synthesis in addition to any chemical reaction forobtaining the desired compound, and to react the reagent for organicsynthesis with excess reaction substrate added in excess to the reactionsystem and byproducts.

Here, “method of organic synthesis reaction” indicates a method forproducing by an organic synthesis reaction a desired compound, and inthe present invention, in particular, it indicates a method using thereagent for organic synthesis disclosed in any of the first to fifthaspects. The method of organic synthesis reaction of the presentinvention is not particularly limited in the used amount of the reagentfor organic synthesis, and can be carried out with any amount, such asthe case of using the reagent for organic synthesis in large industrialamounts, or in the case of using small amounts in testing and research.

Further, the separation step in the method of organic: synthesisreaction according to the sixth embodiment includes a step ofcrystallizing and separating the reagent for organic synthesis, and thereacted reagent for organic synthesis, by means of changing the solutioncomposition and/or by means of changing the solution temperature.Namely, because the reagent for organic synthesis disclosed in any oneof the first to fifth aspects reacts sharply to changes in solventcomposition and/or solvent temperature, by using a means to change thecomposition and/or the temperature of the solvent, the reagent fororganic synthesis or the reacted reagent for organic synthesis can becrystallized, and the reagent for organic synthesis and the reagent fororganic synthesis after reaction can be easily crystallized andseparated in a state where the desired compound of the synthesis remainsin the solution.

As the means for changing the solution composition, for example, themeans of adding another solvent to the reaction system, such as a poorsolvent with respect to the reagent for organic synthesis, or the meansof concentrating the solvent can be mentioned. As a means for changingthe solution temperature, for example, the means of cooling the solutioncan be mentioned.

Effects of The Invention

According to the present invention, the reagent for organic synthesiscan be uniformly dissolved in many organic solvents, and thus can bereacted with a high degree of reactivity with other compounds. Further,after the reaction, it is possible to choose from many separationmethods such as a solid liquid separation method by crystallizing thereagent for organic synthesis, and the reacted reagent for organicsynthesis, or a liquid liquid extraction method by adding a separationsolvent which is immiscible with the reaction solvent, and partitioningthe reagent for organic synthesis and the reacted reagent for organicsynthesis into the separation solvent. Because the separation conditionsof these separation methods can be uniformly determined based on theproperties of the reagent for organic synthesis, it is not necessary toconsider the separation conditions based on the characteristicproperties or the like of each organic synthesis reaction. This not onlysimplifies process development, but also, for example, makes it possibleto accelerate the research and development of pharmaceuticals and thelike by compound library synthesis and the like, and this can in turncontribute to technical innovations in the biochemical industry andchemical industry.

Further, organic synthesis reactions using the organic synthesis reagentof the present invention do not use especially expensive compounds, andthus the organic synthesis reaction can be carried out at low cost.

PREFERRED MODE FOR CARRYING OUT THE INVENTION

Embodiments of the invention are described in detail below. Theseembodiments do not in any way limit the reagent for organic synthesis orthe method of organic synthesis reaction using this reagent of thepresent invention, and appropriate modifications can be made within thescope of the objectives of the present invention.

Reagent for Organic Synthesis

The reagent for organic synthesis according to the present embodiment isshown by Chemical Formula (1) where R₁ to R₅ may be the same ordifferent, and represent a hydrogen, halogen, alkyl group, alkoxylgroup, aryl group, acyl group, thioalkyl group, or dialkylamino groupwith a carbon number of 1 to 30 which may have a substituent group;nitro group, or amino group, and at least two of R₁ to R₅ are alkylgroup, alkoxyl group, acyl group, thioalkyl group, or dialkylamino groupwith a carbon number of 18 to 30 which may have a substituent group.Further, in the formula, X represents a reagent active site having atleast one atom selected from the group consisting of carbon, oxygen,sulfur or nitrogen atom.

Because the above compound has at least two hydrophobic groups selectedfrom the group consisting of alkyl group, alkoxyl group, acyl group, orthioalkyl group with a carbon number of 18 to 30 which may have asubstituent group, it can show sufficient hydrophobicity, and candissolve in a wide range of organic solvents, and further, a compoundwhere the 3-position and 5-position with respect to X (R₂ and R₄) aresubstituted with an alkoxyl group with a carbon number of 18 to 30 isalso stable with respect to acid treatment, and is especially suitablefor the reagent for organic synthesis of the present invention.

Reagent Active Site

In the above Chemical Formula (1), X indicates a reagent active sitehaving at least one atom selected from the group consisting of carbon,oxygen, sulfur, and nitrogen atom. Here, X may also have a structureindicated by the following Chemical Formulas (A) to (M), or (A′) to(M′), Here, Y is an ester bond, ether bond, amide bond, amino bond,thioester bond, sulfide bond, urea bond, carbamate bond or a carbonatebond, or an alkylene group with a carbon number of 1 to 10 which mayhave one of these bonds. Further, in Formulas (M) and (M′), m and n areindependently 0 or 1, Za is a chlorine atom or bromine atom, and Zb is ahydroxyl group, chlorine atom, or bromine atom.

Further, in the reagent for organic synthesis of the present embodiment,a compound where R₂ and R₄ are docosyloxy groups (C₂₂H₄₅O—), and R₁, R₃and R₅ are hydrogen is preferable.

Furthermore, the reagent for organic synthesis of the present embodimentmay be a compound shown by the following Chemical Formula (2).

Namely, the compound shown by the Chemical Formula (2) is a reagent fororganic synthesis shown by the Chemical Formula (1), wherein in theChemical Formula. (1), X is a hydroxymethyl group, R₂ and R₄ aredocosyloxy (C₂₂H₄₅O—), R₁, R₃ and R₅ are hydrogen.

Here, the compound shown by the Chemical Formula (2) has a hydroxylgroup, and because it shows nucleophilicity, it can be used as anucleophilic scavenger.

Manufacturing Method of the Reagent for Organic Synthesis

The manufacturing method of the reagent for organic synthesis indicatedin the above formula is not particularly limited, but it can generallybe synthesized by various reactions such as the following.

A compound having a plurality of phenolic hydroxyl groups such as methylgallic acid, and long chain brominated alkyl are reacted inN,N-dimethylformamide, under basic conditions, to yield an aromaticcompound having an alkoxy group. Next, an ester site is converted to theother substituting group to induce the desired compound by a functionalgroup substitution by a publicly known means, or the aromatic compoundis combine to a specially prepared reagent active site in an arbitrarybounded form to manufacture the reagent of the present embodiment.

Method of Organic Synthesis Reaction

The reagent for organic synthesis of the present embodiment can be usedby the same method of use as the reagent used in the liquid phaseorganic synthesis reactions of the prior art which do not have ahydrophobic carrier group. Namely, in a state wherein the reactionsubstrate to be reacted is dissolved or dispersed in a solvent, areagent for organic synthesis having a hydrophobic carrier group isadded, and a reaction is carried out. Here, as the solvent used in thereaction system, it is possible to use a general organic solvent in thereaction, but because the reactivity is increased as the solubility ofthe reagent for organic synthesis in the solvent increases, it ispreferable to select a solvent for which the solubility of the reagentfor organic synthesis is high. Specifically, tetrahydrofuran,dichloromethane, diethylether, hexane, cyclohexane,N,N-dimethylformamide and the like are preferable, but it is notparticularly limited to this. To confirm the progress of the reaction,the same methods used for general liquid phase organic synthesisreactions can be applied. Namely, thin layer silica gel chromatography,high speed liquid chromatography, and the like can be used to track thereaction.

Reaction Step

In the reaction step, by reacting a specified reaction substrate and thereagent for organic synthesis, or by using the reagent for organicsynthesis as a reaction accelerator in a specified chemical reaction, itis possible to obtain the desired compound. Further, it is possible tocarry out an arbitrary chemical reaction for obtaining the desiredcompound, and reacting residual reaction substrate added in excess tothe reaction system, and byproducts, with the reagent for organicsynthesis.

Use of the Reagent for Organic Synthesis as a Synthesis Building Block

In the case of using the reagent for organic synthesis as a synthesisbuilding block, for example, consideration can be given to using thereagent for organic synthesis as a reaction substrate in a nucleophilicaddition reaction, nucleophilic substitution reaction, dehydrationcondensation reaction, and the like. As a reagent for organic synthesisreaction which can be used in such a reaction, there is no particularlimitation, and for example, in the reagent for organic synthesis shownin Chemical Formula (1), reagent for organic synthesis where X is areagent active site shown by (A) to (H) or (A′) to (H′) can beMentioned. As the solvent used for the reaction, any solvent which canbe ordinarily used for these reactions can be used, and in the presentembodiment, from the point of solubility of the reagent for organicsynthesis having a hydrophobic carrier group, it is possible to usetetrahydrofuran, dichloromethane, cyclohexane/N,N-dimethylformamidemixed solvent and the like.

Use or the Reagent for Organic Synthesis as a Reaction Accelerator

The reagent for organic synthesis of the present embodiment can be usedas a reaction accelerator. The effect as a reaction accelerator dependson the properties of the reagent active site of the reagent for organicsynthesis, for example, the degree of acidity and basicity, thecatalytic activity and the like. A reagent active site having suchproperties can be introduced on a hydrophobic carrier group by using asynthesis building block.

There is no particular limitation on the reagent for organic synthesiswhich can be used as a reaction accelerator, and for example, in thereagent for organic synthesis shown by Chemical Formula (1), a reagentfor organic synthesis where X is a reagent active site shown by (I),(J), (I′) or (J′) can be mentioned. These reagents for organic synthesisshow strong basicity, and by scavenging active hydrogens of the reactionsubstrate, can accelerate nucleophilic reactions, deprotectingreactions, esterification reactions of carboxylic acids, alkylationreactions of active methyl, alkylation reactions of secondary amines,alkylation reactions of phenols, and alkylation reactions of thiols.

Acceleration of Deprotecting Reactions

A reagent for organic synthesis having strong basicity can be used forexample, for the deprotecting reaction of an Fmoc group(9-fluorenylmethoxycarbonyl group), known as a protecting group of aminogroups, and the like, but it is not particularly limited to thesereactions. As the solvent used for the reaction, any one which can beordinarily used for such reactions can be used, and in the presentembodiment, from the point of solubility of the reagent for organicsynthesis having a hydrophobic carrier group, it is possible to usetetrahydrofuran, dichloromethane, cyclohexane/N,N-dimethylformamidemixed solvent and the like.

The added amount of the reagent for organic synthesis used in thereaction can be appropriately set by one skilled in the art inconsideration of the solubility of the reagent for organic synthesis inthe used solvent, the equilibrium constant of the acid-base equilibriumof the basic groups, the reaction stoichiometry, and the like, andgenerally, it is preferable to add one to five times the theoreticallyrequired amount.

Further, a reagent for organic synthesis having a strong basicity, inthe same was as its use as an accelerator or a deprotecting reaction,can be used as an accelerator of a nucleophilic reaction, deprotectingreaction, esterification reaction of a carboxylic acid, alkylationreaction of an active methylene, alkylation reaction of an amine,alkylation reaction of a phenol, alkylation reaction of a thiol, and thelike. In these cases, it is possible to use the same solvent as thesolvent used for a deprotecting reaction, and further, it is possible toaccelerate the reaction by adding the reagent for or in an amount whichis the same as that of the reagent for organic synthesis used toaccelerate deprotecting reactions.

Use of the Reagent for Organic Synthesis as a Condensation Agent

The reagent for organic synthesis of the present embodiment can be usedas a condensation agent. For example, the reagent for organic synthesiscan be used as condensation agent replacing the triphenylphosphine anddiethyl azodicarboxylate required in the dehydration condensationreaction publicly known as the Mitsunobu reaction. As such a reagent fororganic synthesis, for example, in the reagent for organic synthesisshown in Chemical Formula (1), a reagent for organic synthesis where Xis a reagent active site shown by (K), (L), (K′), or (L′) can bementioned.

The dehydration condensation reaction which can be used in the presentembodiment is not particularly limited, and for example, ester synthesisreactions, amide synthesis reactions and ether synthesis reactions canbe mentioned. The solvent used for the reaction is not particularlylimited if it is a solvent which can be ordinarily used for suchreactions, and in the present embodiment, from the point of solubilityof the reagent for organic synthesis having a hydrophobic carrier group,it is possible to use tetrahydrofuran, dichloromethane,cyclohexane/N,N-dimethylformamide mixed solvent and the like.

The added amount of the reagent for organic synthesis used in thereaction can be appropriately set by one skilled in the art inconsideration of, for example, in the case of a Mitsunobu reaction, thesolubility of the reagent for organic synthesis with respect to the usedsolvent, the stoichiometry of the Mitsunobu reaction, and the like, andin the case of adding the reagent for organic synthesis as a substitutesubstance of triphenylphosphine, it is preferable to add from 1 to 5equivalents with respect to one equivalent of the dehydrated hydroxylgroup, and in the case of adding as a substitute substance for diethylazodicarboxylate, it is preferable to add from 1 to 5 equivalents withrespect to one equivalent of the dehydrated hydroxyl group.

Use of the Reagent for Organic Synthesis as a Nucleophilic Scavenger andan Electrophilic Scavenger

By using the reagent for organic synthesis of the present embodiment asa nucleophilic scavenger and an electrophilic scavenger, it is possibleto capture electrophilic reagents or nucleophilic reagents added inexcess and remaining unreacted in the reaction liquid, and compoundshaving electrophilicity and nucleophilicity produced as byproducts inthe chemical reaction. Alternatively, in the case of using the reagentfor organic synthesis of the present embodiment as a nucleophilicscavenger, and an electrophilic scavenger, it is also possible to bondit to the unreacted reaction substrate, and make the reaction proceed onthe reagent for organic synthesis. The reagent for organic synthesiswhich can be used in such reactions is not particularly limited, and forexample, in the reagent for organic synthesis shown in Chemical Formula(1), a reagent for organic synthesis wherein the reagent active site Xis shown by (A) to (C) or (A′) to (C) if a nucleophilic scavenger, orthe reagent active site X is shown by (D) to M and (M), or (D′) to (H′)and (M′) if an electrophilic scavenger, can be mentioned.

The added amount of the reagent for organic synthesis used in thereaction can be appropriately set by one skilled in the art inconsideration of the solubility of the reagent for organic synthesiswith respect to the used solvent, and the electrophilicity andnucleophilicity of the compound to be captured and the like, and it ispreferable to add from 1 to 5 equivalents of the reagent for organicsynthesis with respect to one equivalent of the expected residual amountof the nucleophilic or electrophilic reaction substrate.

For the case of using the reagent for organic synthesis of the presentembodiment as a nucleophilic scavenger, for example, a form of use suchas the following can be mentioned.

Namely, in the case of carrying out a peptide synthesis reaction usingan active amino acid in an N,N-dimethylformamide/propionitrile mixedsolvent, a peptide bond is formed when adding an excess amount of theactivated amino acid with respect to the N terminal amino group of thepeptide. Because the excess active amino acid remaining in the reactionsystem has electrophilicity, it is easy to form an ester bond with thisby adding the compound shown in Chemical Formula (2). After thereaction, by adding a solvent such as cyclohexane or the like, it ispossible to recover the nucleophilic scavenger bonded to the activeamino acid from the amide layer, and a peptide to which 1 amino acidresidue is attached, at the N terminal of the peptide before thereaction, remains in the reaction system.

Use of the Reagent for Organic Synthesis as a Peptide Synthesis Reagent

Among the reagents for organic synthesis of the present embodiment,those shown by Chemical Formula (1) where X indicates (M) or (M′) can beused as electrophilic scavengers, and especially, can be used as peptidesynthesis reagents. In the case of use as a peptide synthesis reagent,in the reagent active site shown by Chemical Formulas (M) and (M′), acarbon atom bonded to the hydroxyl group in the reagent active site, aswell as a carbon atom bonded to the halogen atom which is not directlybonded to the benzene ring, have electrophilicity, and thus can bondwith the carboxyl group of the amino acid, and thus the peptidesynthesis reaction can be carried out by sequentially forming bonds toan activated amino acid in the state wherein the carboxyl group isbonded to the reagent for organic synthesis.

At the completion of the peptide synthesis reaction, by adding acid tothe reagent for organic synthesis separated from the reaction system, itis possible to easily separate only the peptide. Here, the reagent fororganic synthesis having a reagent active site (M) or (M′) does notactivate the carbonyl group when the amino acid is bonded to the reagentfor organic synthesis, and thus there is no generation of intermediateshaving an oxazolone skeleton which would lead to racimization of the αcarbon, and thus in the process of peptide synthesis, racimization ofthe peptide does not occur.

Further, applications of the reagent for organic synthesis having areagent active site (M) or (M′) are not limited to applications as areagent for peptide synthesis. Specifically, for example, applicationsas a hydrophobic carrier group, by reacting the reagent for organicsynthesis having a reagent active site with the desired compound, can bementioned. Such reagents for organic synthesis used as a hydrophobiccarrier group are also included within the scope of the presentinvention.

Use of the Reagent for Organic Synthesis as a Metal Ligand

By using the reagent for organic synthesis as a metal ligand, thereagent for organic synthesis can coordinate with and capture metal ionsadded to the reaction system as catalysts or the like. The reagent fororganic synthesis which can be used for such a reaction is notparticularly limited, and for example, in the reagent for organicsynthesis shown by Chemical Formula (1), a reagent for organic synthesiswhere X is a reagent active site shown by (K) or (K′) can be mentioned.

The added amount of the reagent for organic synthesis used in thereaction can be appropriately set by one skilled in the art inconsideration of the solubility of the reagent for organic synthesiswith respect to the solvent, and the normal coordination number of themetal ion and the like, and it is preferable to add from 1 to 5equivalents of the reagent for organic synthesis with respect to oneequivalent of the added metal ion.

For the case of using the reagent for organic synthesis as anucleophilic scavenger, electrophilic scavenger, or metal ion ligand, inthe chemical reaction preceding the reaction for trapping the excesscompounds and the like, it is possible to use a solvent commonly used inthis reaction, and in the present embodiment, from the point of thesolubility of the reagent for organic synthesis having a hydrophobiccarrier group, it is preferable to use tetrahydrofuran, dichloromethane,a cyclohexane/N,N-dimethylformamide mixed solvent or the like as thesolvent.

Separation Step

The reagent for organic synthesis of the present embodiment reactssharply to changes in the solution composition and/or temperature, andcrystallizes. Because of this, it is possible to crystallize the reagentfor organic synthesis using the means of changing the composition and/ortemperature of the solution. Further, the separation step of the reagentfor organic synthesis can by carried out by liquid liquid extractionseparation, by adding a separation solvent which is immiscible with thereaction solvent used in the reaction step, but which can easilydissolve the reagent for organic synthesis.

Separation by Changing the Solution Composition

As a preferred means for changing the solution composition, for example,the means of adding a poor solvent for the reagent for organic synthesisto the reaction solution can be mentioned. Here, by adding a solventwith high affinity for the reaction solvent, there is no phaseseparation of the liquid phase, and thus is it possible to easily changethe solution composition. As the poor solvent, it is possible to use anysolvent, and it is possible to use the same solvent used as the reactionsolvent, and a solvent which differs form the reaction solvent. Forexample, in the case of using dichloromethane, tetrahydrofuran anddiethylether or the like as the reaction solvent, it is possible to useacetonitrile, N,N-dimethylformamide, and methanol and the like as thepoor solvent. By adding the poor solvent to the reaction solvent, thepolarity of the solution increases, and the reagent for organicsynthesis, and the reacted reagent for organic synthesis can crystallizeand solid liquid separation becomes possible. When carrying out thesolid liquid separation, it is possible to use a suction filter such as,for example, separatory funnel, and in order to complete the separationof the products from a reagent having a hydrophobic carrier group, anoctadecylsilylated (ODS) silica gel filter or an ODS short column may beused.

Separation by Concentration of the Solution

As another preferable means for changing the solution composition, forexample, the means of concentrating the solvent of the solution in whichthe reagent for organic synthesis, and the reacted reagent for organicsynthesis are dissolved, can be mentioned. Here, concentrating refers todistilling away a part of the solvent. When distilling a part of thesolvent, it is preferable to carry out the distillation within a rangewherein the reagent for organic synthesis, and the reacted reagent fororganic synthesis crystallize, while the synthesized desired compounddoes not crystallize. These conditions can be appropriately set by oneskilled in the art in consideration of the added amount of the reagentfor organic synthesis, the estimated produced amount of the desiredcompound, the solubility of each compound and the like.

Separation by Changing the Solution Temperature

In the separation step, by changing the solution temperature, it ispossible to crystallize and separate the reagent for organic synthesisand the reacted reagent for organic synthesis. In the presentembodiment, as a preferably used means for changing the solutiontemperature, there is no particular limitation so long as it is a meansfor changing the temperature of the solution in which the reagent fororganic synthesis and the reacted reagent for organic synthesis aredissolved. Specifically, the means of cooling the solution can bementioned. For example, in the case of using cyclohexane as the reactionsolvent, by cooling to 5° C. or less, it is possible to crystallize thereagent for organic synthesis and the reacted reagent for organicsynthesis. Further, in the case of using N,N-dimethylformamide as thereaction solvent, by heating in the reaction step, the solubility of thereagent for organic synthesis increases, and by cooling after thereaction, the reagent for organic synthesis and the reacted reagent fororganic synthesis can be crystallized.

In the case of crystallizing the reagent for organic synthesis bychanging the solution composition and the solution temperature, byadding octadecylsilylated silica gel, glass beads or the like ascrystallization seeds, it is possible to easily form the crystals.

Separation by Liquid Liquid Extraction

In the separation step, by adding a separation solvent which does notmix with the reaction solvent in which the reagent for organic synthesisis dissolved in the reaction step, and for which the solubility of thereagent for organic synthesis is greater than the solubility of thereagent for organic synthesis in the reaction solvent, it is possible todissolve the reagent for organic synthesis and the reacted reagent fororganic synthesis in the separation solvent. By separating with aseparatory funnel the separation solvent in which the reagent fororganic synthesis, and the reacted reagent for organic synthesis aredissolved, it is possible to easily separate the reagent for organicsynthesis, and the reacted reagent for organic synthesis from thereaction solvent.

In the present embodiment, the separation solvent which can be used isnot particularly limited, and in the case of using acetonitrile,propionitrile, and N,N-dimethylformamide or the like as a reactionsolvent, for example, cyclohexane, and decalin or the like can be used.

Namely, for example, in the case of using N,N-dimethylformamide as thereaction solvent, by adding cyclohexane as the separation solvent to thereaction system after the completion of the chemical reaction, heating,and then cooling, the reagent for organic synthesis, and the reactedreagent for organic synthesis are selectively distributed into thecyclohexane phase. By separating the cyclohexane phase with a separatoryfunnel, it is possible to obtain an N,N-dimethylformamide solution fromwhich the reagent for organic synthesis, and the reacted reagent fororganic synthesis have been removed.

In the method of organic synthesis reaction of the present embodiment,after separating the reagent for organic synthesis, it is possible tofurther carry out a process for separating the reagent for organicsynthesis and an atomic group bonded to the reaction active site, and toisolate the separated atomic group. In such a case, as a reagent whichcan be used when separating the reagent for organic synthesis and theatomic group bonded to the reaction active site, trifluoroacetate, andacids such as hydrochloric acid and the like; bases such as sodiumhydroxide; as well as hydrogenation catalysts such as palladium and thelike can be mentioned. Among these, trifluoroacetate can be preferablyused.

EXAMPLES

The present invention is explained below with reference to the followingExamples, but the present invention is not in any way limited by theseexamples.

Example 1 Synthesis of an Amine Having a Hydrophobic Carrier Group

One gram of 2,4-dihydroxybenzaldehyde, 8.4 g of 1-bromodocosane, and 6 gof potassium carbonate were dissolved in 20 ml of N,N-dimethylformamide,and reacted for 8 hours under a nitrogen gas flow at 80° C. Afterconfirming the completion of the reaction by thin layer chromatography,20 ml of toluene and 10 ml of water were added to the reaction liquidand stirred for 5 min at 80° C. The toluene layer was separated with aseparatory funnel and after removal by distillation of the solvent, 50ml of methanol were added and crystals were precipitated. This solutionwas subjected to suction filtration with a separatory funnel and 6.97 gof crude crystals were obtained. After dissolving the crude crystals in200 ml of hexane at 70° C. and recrystallizing at room temperature,suction filtration was again carried out with a separatory funnel, and4.7 g of the desired compound 3 were obtained. The yield was 85%.Compound 3; 2,4-bis(docosyloxy)benzaldehyde.

Then, 1.9 g of compound 3 were set aside and dissolved indichloromethane, and 500 mg of hydroxyamine hydrochloride, and an excessamount of triethylamine were added and reacted for 6 hours at roomtemperature. After the completion of the reaction, the solution wasconcentrated, and 50 ml of acetonitrile were added and the product wascrystallized. This solution was suction filtered with a separatoryfunnel and 1.9 g of compound 4 were obtained. The yield was 98%.Compound 4; 2,4-bis(docosyloxy)benzaldehyde oxime.

Next, 770 mg of compound 4 were set aside and dissolved intetrahydrofuran, 150 mg of lithium aluminum hydride were added at roomtemperature and stirred, and after this, heating and refluxing werecarried out. After the completion of the reaction was confirmed by thinlayer chromatography, 5 ml of methanol and 50 ml of toluene were addedand the organic layer was washed with an aqueous solution of 1 Nhydrochloric acid, neutralized with a saturated sodium hydrogencarbonate solution, and washed with a saturated saline solution. Theorganic layer was separated and vacuum distillation removed, and afterthis, 50 ml of methanol were added and crystals precipitated. Thissolution was suction filtered with a separatory funnel and 719 mg ofcompound 5 were obtained. The yield was 95%. Compound 5;(2,4-bis(docosyloxy)phenyl)methane amine.

The above reactions are shown below.

Structural Analysis of Compound 3

¹H-NMR (CDCl₃, 300 MHz) δ 10.32 (1H, s), 7.78 (1H, d, J=8.62 Hz), 6.50(1H, dd J=8.62, 2.20 Hz), 6.41 (1H, d, J=2.20 Hz), 4.04 (1H, d, J=6.60Hz), 3.99 (1H, d, J=6.60 Hz), 1.81 (4H, m), 1.51-1.18 (76H, m), 0.88(6H, t, J=6.60 Hz)

Structural Analysis of Compound 4

¹H-NMR (CDCl₃, 300 MHz) δ 8.45 (1H, s), 7.65 (1H, d, J=8.40 Hz), 6.46(1H, dd J=8.40, 2.20 Hz), 3.96 (2H, t, J=6.42 Hz), 3.95 (2H, t, J=6.42Hz), 1.78 (4H, m), 1.50-1.15 (76H, m), 0.88 (6H, t, J=6.80 Hz)

Structural Analysis of Compound 5

¹H-NMR (CDCl₃, 300 MHz) δ 8.45 (1H, s), 7.65 (1H, d, J=8.40 Hz), 6.46(1H, dd J=8.40, 2.20 Hz), 3.96 (2H, t, J=6.42 Hz), 3.95 (2H, t, J=6.42Hz), 1.78 (4H, m), 1.50-1.15 (76H, m), 0.88 (6H, t, J=6.80 Hz).

Example 2 Synthesis of an isocyanate Having a Hydrophobic Carrier Group

An amount of 371 mg (0.4 mmol) of 3,4,5-tris(octadecyloxy)benzoic acidwas dissolved in 5 ml of toluene, and mixed with 412 mg (1.50 mmol) ofdiphenylphosphoryl azide (DPPA) and 30 mg (0.4 mmol) of triethylamine.This was stirred for 3 hours at room temperature, and then, heated to90° C., and further reacted for 3.5 hours. After the completion of thereaction, acetonitrile was added, and after the precipitation ofcrystals, suction filtration was carried out with a separatory funneland 333 mg of compound 6 were obtained. The yield was 90%. Compound 6;5-isocyanate-1,2,3-tris(octadecyloxy)benzene.

The above reactions are shown below.

Structural Analysis of Compound 6

¹H-NMR (CDCl₃, 400 MHz) δ 6.20 (2H, s), 3.98-3.92 (6H, m), 1.82-1.69(6H, m), 1.49-1.23 (84H, m), 0.88 (9H, t, J=6.60 Hz)

Example 3 Synthesis of a Chloroformate Having a Hydrophobic CarrierGroup

An amount of 4.43 g of methyl 3,5-bis(docosyloxy)benzoate was dissolvedin 100 ml of tetrahydrofuran, and 240 mg of lithium aluminum hydridewere introduced and stirred at room temperature. After the completion ofthe reaction was confirmed by thin layer chromatography, 1 ml ofmethanol was added and the reaction was stopped. After this, 30 ml of 1N hydrochloric acid was added, and the extracted organic layer waswashed two times with 30 ml of 1 N hydrochloric acid, once with 30 ml ofa saturated aqueous solution of sodium hydrogen carbonate, and twicewith 30 ml of saturated saline solution, and dried with magnesiumsulfate. After vacuum distillation of the solution, 100 ml of methanolwere added and crystals precipitated, and suction filtration was carriedout using a separatory funnel to obtain 3.62 g of compound 7. The yieldwas 80%. Compound 7; 3,5-bis(docosyloxy)benzyl alcohol

An amount of 5 g of compound 7 was dissolved in 50 ml of toluene, 4.86 gof triphosgene were added, and reacted for 2 hours under a nitrogen gasflow at room temperature. After this, the reaction liquid was heated to40° C., and further stirred for 1 hour. After the completion of thereaction was confirmed by thin layer chromatography, drying was carriedout for 2 hours at 3 mmHg under a vacuum pump at 40° C. to obtain 5.1 gof compound 8. The yield was 94%. Compound 8;3,5-bis(docosyloxy)benzylcarbonochloridate

The above reactions are shown below.

Structural Analysis of Compound 7

¹H-NMR (CDCl₃, 300. MHz) δ 6.49 (2H, d, J=2.20 Hz), 6.37 (1H, t, J=2.20Hz), 4.60 (2H, s), 3.92 (4H, t, J=6.60 Hz), 1.76 (4H, m), 1.49-1.18(76H, m), 0.88 (6H, t, J=6.60 Hz)

Structural Analysis of Compound 8

¹H-NMR (CDCl₃, 300 MHz) δ 6.49 (2H, d, J=2.20 Hz), 6.45 (1H, t, J=2.20Hz), 5.20 (2H, s), 3.93 (4H, t, J=6.79 Hz), 1.76 (4H, m), 1.52-1.13(76H, m), 0.88 (6H, t, J=6.60 Hz)

Example 4 Synthesis of a Carbamate Having a Hydrophobic Carrier Group

An amount of 756 mg (1.0 mmol) of the compound 7 synthesized in Example3 was set aside, and dissolved in 20 ml of dichloromethane. Then, 810 mg(5.0 mmol) of 1,1′-carbonyldiimidazole was added, and stirred for 4hours at room temperature. After the completion of the reaction wasconfirmed by thin layer chromatography, the solvent was distilled undera vacuum, acetonitrile was added, and crystallization occurred. This wassuction filtered using a separatory funnel, and 850 mg of compound 9were obtained. The yield was 99%. Compound 9; 3,5-bis(docosyloxy)benzyl1H-imidazole-1-carboxylate

The above reactions are shown below.

Structural Analysis of Compound 9

¹H-NMR (CDCl₃, 400 MHz) δ 8.15 (1H, m), 7.44 (1H, m), 7.06 (1H, m), 6.53(214, d, J=2.21 Hz), 6.46 (1H, t, J=2.21 Hz), 5.32 (2H, s), 3.93 (4H, t,J=6.42H), 1.75 (4H, m), 1.49-1.16 (76H, m), 0.88 (6H, t, J=6-97 Hz)

Example 5 Synthesis of a Bromine Compound Having a Hydrophobic CarrierGroup

To a dried recovery flask, 915.0 mg (1 mmol) of3,4,5-trisoctadecyloxybenzyl alcohol were added, and dissolved in 10 mlof dichloromethane. Then, 406.3 mg (15 mmol) of phosphorus tribromidewere added, and stirred for 3 hours at room temperature. Afterconfirming the completion of the reaction by thin layer chromatography,1 ml of water was added and the reagent was deactivated. After this,liquid liquid extraction was carried out with hexane, and then washingwas carried out with a saturated saline solution, and an organic phasewas obtained. The solvent was distilled under a vacuum from this organicphase, and suction filtration was carried out using a separatory funnel,and 968.1 g of compound 10 were obtained. The yield was 99%. Compound10; 3,4,5-trisoctadecyloxybenzylbromide

The above reactions are shown below.

Structural Analysis of Compound 10

¹H-NMR (CDCl₃, 400 MHz) δ 6.57 (2H, s), 4.43 (2H, s), 3.98-3.92 (6H, m),1.82-1.69 (6H, m), 1.50-1.42 (6H, m), 1.33-1.23 (84H, m), 0.88 (9H, t,J=7.0 Hz)

Infrared Absorption Spectrum (KBr) δ 2954, 2920, 2848, 1591, 1504, 1466,1441, 1394, 1246, 1213, 1115 (units cm⁻¹)

Example 6 Synthesis of a Basic Compound Having a Hydrophobic CarrierGroup

Into a dried recovery flask 1.46 g (1.5 mmol) of compound 10 synthesizedin Example 5 were set aside and dissolved in 20 ml ofN,N-dimethylformamide. Then, 443.1 mg (2 equivalents) of potassiumcarbonate, 369.4 mg (1 equivalent) of tetrabutylammonium iodide, and1.05 g (5 equivalents) of 1,5,7-triazabicyclo[4,4,0]deca-5-ene wereadded, and stirred for 4 hours at 80° C. After the completion of thereaction was confirmed by thin layer chromatography, liquid liquidextractions were carried out with hexane, and then with a saturatedsaline solution, and an organic phase was obtained. This organic phasewas distilled under a vacuum, methanol was added and crystallizationoccurred, and then suction filtration was carried out with a separatoryfunnel, and 1.3 g of compound 11 were obtained. The yield was 84%Compound 11;1-(3,4,5-tris(octadecyloxy)benzyl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine.

The above reactions are shown below.

Structural Analysis of Compound 11

¹H-NMR (CDCl₃, 600 MHz) δ 6.46 (2H, s), 4.49 (2H, s), 3.94 (4H, t,J=6.6), 3.91 (2H, t, J=6.6), 3.41 (2H, t, 3.18 (2H, t, J=5.9), 3.13 (2H,t, J=5.9), 3.03 (2H, t, J=5.9), 1.89 (4H, m), 1.79-1.70 (6H, m),1.48-1.43 (6H, m), 1.35-1.21 (84H, m), 0.87 (9H, t, J=7)

Infrared Absorption Spectrum (KBr): 2954, 2916, 2850, 1593, 1504, 1468,1435, 1381, 1228, 1115, 835 (units: cm⁻¹)

Example 7 Synthesis of a Triphenylphosphine Having a Hydrophobic CarrierGroup

An amount of 756 mg (1.0 mmol) of the compound 7 synthesized in Example3 was set aside and dissolved in 20 ml of dichloromethane. Then, 612 mg(2.0 mmol) of 4-(diphenylphosphino) benzoic acid, 25 mg (0.2 mmol) ofdimethylaminopyridine, 631 mg (5.0 mol) of dicyclohexylcarbodiimide wereadded, and stirred for 4 hours at room temperature. After the completionof the reaction was confirmed by thin layer chromatography, the solventwas distilled under a vacuum, and acetonitrile was added andcrystallization occurred, and suction filtration was carried out using areparatory funnel, and 1.0 g of compound 12 were obtained. The yield was96%. Compound 12; 3,5-bis(docosyloxy)benzyl-4-(diphenylphosphino)benzoicacid.

The above react ions are shown below.

Structural Analysis of Compound 12

¹H-NMR (CDCl₃, 400 MHz) δ 8.00 (2H, dd, J=1.28 Hz), 7.39-7.27 (12H, m),6.53 (2H, d, J=2.01 Hz), 6.41 (1H, t, J=2.01 Hz), 5.26 (2H, s), 392 (4H,m), 1.75 (4H, m), 1.49-1.14 (76H, m), 0.88 (6H, t, J=6.97 Hz)

Example 8 Synthesis of an Azodicarboxylate Ester Having a HydrophobicCarrier Group

An amount of 850 mg (1.0 mmol) of the compound 9 synthesized in Example4 was set aside, and dissolved in 10 ml of toluene. Then, 312 mg (3.0mmol) of ethyl carbazate, and 303 mg (3.0 mmol) of triethylamine wereadded, and stirred for 18 hours at 120° C. After completion of thereaction, the solvent was distilled, and 100 ml of acetonitrile wereadded, and the precipitated crystals were suction filtered, and 798 mgof compound 13 were obtained. The yield was 90%. Next, 888 mg ofcompound 12 (1.0 mmol) were set aside and after dissolving in 10 ml ofdichloromethane, 644 mg (2.0 mmol) of iodobenzene acetate were added,and stirred for 3 hours at room temperature. After confirming thecompletion of the reaction by thin layer chromatography, the solvent wasdistilled under a vacuum, and 10 ml of acetonitrile were added andcrystallization occurred. Suction filtration was carried out using aseparatory funnel and the crystals were separated, and 620 mg ofcompound 14 were obtained. The yield was 70%. Compound 13;1-(3,5-bis(docosyloxy)benzyl)-2-ethylhydrazine-1,2-dicarboxylate.Compound 14;1-(3,5-bis(docosyloxy)benzyl)-2-ethyldiazine-1,2-dicarboxylate.

The above reactions are shown below.

Structural Analysis of Compound 13

¹H-NMR (CDCl₃, 400 MHz) δ 6.45 (2H, d, J=2.20 Hz), 6.37 (1H, t, J=2.20Hz), 5.07 (2H, s), 4.19 (2H, q, J=7.34 Hz), 3.89 (4H, t, J=6.60 Hz),1.73 (4H, m) 1.46-1.14 (76H, m), 0.86 (6H, t, J=6.60 Hz)

Structural Analysis of Compound 14

¹H-NMR (CDCl₃, 400 MHz) δ 6.52 (2H, d, J=2.20 Hz), 6.39 (1H, t, J=2.20Hz), 5.32 (2H, s), 4.49 (2H, m), 3.89 (4H, m), 1.73 (4H, m), 1.46-1.14(76H, m), 0.86 (6H, t, J=6.60 Hz)

Example 9 Scavenging of 4-Chlorobenzylamine Using an Isocyanate Having aHydrophobic Carrier Group

Amounts of 141 mg (1.0 mmol) of 4-chlorobenzylamine and 183 mg (1.0mmol) of N-(4-chlorobenzyl)acetamide were dissolved in 20 ml ofdichloromethane. To the solution, 1.0 g (1.1 mmol) of the compound 6synthesized in Example 2 were added, and after stirring for 10 minutes,50 ml of acetonitrile were added. After distilling the dichloromethaneunder a vacuum at room temperature, the crystals were filtered with aseparatory funnel. On distilling the filtrate,N-(4-chlorobenzyl)acetamide was quantitatively recovered, and thecrystals were compound 15. Compound 15;1-(4-chlorobenzyl)-3-(3,4,5-tris(octadecyloxy)phenyl)urea

The above reactions are shown below.

Structural Analysis of Compound 15

¹H-NMR (CDCl₃, 300 MHz) δ 7.10 (4H, m), 6.45 (2H, s), 6.39 (2H, m), 3.90(6H, m), 1.77 (6H, m), 1.53-1.17 (90H, m), 0.86 (6H, t, J=6.60 Hz)

Example 10 Synthesis Reaction of Diketopiperazine Using a Base Having aHydrophobic Carrier Group

An amount of 278 mg (0.2 mmol) of3,4,5-tris(octadecyloxy)benzyl-1-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoyl)pyrrolidine-2-carboxylatewere dissolved in 20 ml of dichloromethane. To this, 205 mg (0.2 mmol)of the compound 11 synthesized in Example 6 were added, and stirred for7 hours. After the reaction, 50 ml of acetonitrile were added. Afterdistilling the dichloromethane under a vacuum at room temperature, thecrystals were filtered with a separatory funnel. The filtrate was vacuumdistilled, and 35.1 mg of diketopiperazine were obtained. The yield was72%.

Comparative Example 1 Synthesis Reaction of Diketopiperazine Using aBase Carried on a Polystyrene

An amount of 278 mg (0.2 mmol) of3,4,5-tris(octadecyloxy)benzyl-1-(2-(((9H-fluorene-9-yl)methoxy)carbonylamino)-3-phenylpropanoyl)pyrrolidine-2-carboxylatewere dissolved in 20 ml of dichloromethane. To this, 600 mg (amino groupequivalent 1.2 mmol) of “TBD-methyl polystyrene” (manufactured byNovabiochem) was added and stirred for 21 hours. The reaction liquid wasfiltered, and after distilling the solvent, 50 ml of acetonitrile wereadded. After filtering the crystals in a separatory funnel, the filtratewas vacuum distilled, and 18.5 mg of diketopiperazine were obtained. Theyield was 38%.

Comparative Example 2 Synthesis Reaction of Diketopiperazine Using aBase Carried on a Silica Gel

An amount of 278 mg (0.2 mmol) of3,4,5-tris(octadecyloxy)benzyl-1-(2-(((9H-fluorene-9-yl)methoxy)carbonylamino)-3-phenylpropanoyl)pyrrolidine-2-carboxylatewas dissolved in 20 ml of dichloromethane. To this, 1200 mg (amino groupequivalent 1.2 mmol) of “Si-TBD” (manufactured by Sigma Aldrich) wasadded and stirred for 21 hours. The reaction liquid was filtered, andafter the distillation of the solvent, 50 ml of acetonitrile were added.After filtration of the crystals with a separatory funnel, the filtratewas vacuum distilled, and 7.3 mg of diketopiperazine were obtained. Theyield was 15%.

The reactions of Example 10, and Comparative Examples 1 and 2 are shownbelow.

A comparison of the yields of Example 10, and Comparative Examples 1 and2 is shown in Table 1.

TABLE 1 Comparative Comparative Example 10 Example 1 Example 2 Amount ofBase 1 6 6 (Equivalent) Reaction Time (hr) 7 21 21 Yield (%) 72 38 15

Example 11 Mitsunobu Reaction Using an Azodicarboxylate Ester Having aHydrophobic Carrier Group

Into an recovery flask, 16 mg (0.1 mmol) of 2-(4-methoxyphenyl)aceticacid, and 7 mg (0.1 mmol) of isopropanol were added, and dissolved in 5ml of tetrahydrofuran. To this, 52 mg (0.2 mmol) of triphenylphosphine,and 177 mg (0.2 mmol) of the compound 14 of Example 8 were added, andstirred for 24 hours at room temperature. The solvent was distilledunder a vacuum, acetonitrile was added, and filtration was carried outwith an octadecylsilyl silica packed syringe, and from the filtrate,16.7 mg of isopropyl-2-(4-methoxyphenyl)acetate was obtained. The yieldwas 70%.

The above reactions are shown below.

Example 12 Peptide Synthesis Reaction

An amount of 785 mg (1.0 mmol) of methyl 3,5-bis(docosyloxy)benzoate wasdissolved in 20 ml of tetrahydrofuran, and 18 ml (9 equivalents) of4-chlorophenylmagnesiumbromide tetrahydrofuran solution was added, andstirring was carried out for 2 hours at 76° C. After confirming thecompletion of the reaction by thin layer chromatography, 30 ml of 1 Nhydrochloric acid was added and the reaction was stopped. After this,extraction was carried out 3 times with 30 ml of hexane, and theobtained organic phase was further washed one time with 30 ml of 1 Nhydrochloric acid, one time with saturated sodium hydrogen carbonate,and one time with saturated saline solution, and dried with magnesiumsulfate. After vacuum distillation of the solvent, 100 ml of methanolwas added and crystals were precipitated, and suction filtration wascarried out with a separatory funnel to obtain 780 mg of compound 16.The yield was 80%. Compound 16;3,5-bis(docosyloxy)phenyl-4,4-dichlorophenyl alcohol.

Structural Analysis of Compound 16

¹H-NMR (CDCl₃, 400 MHz) δ 7.30-7.26 (4H, m), 7.23-7.17 (4H, m),6.44-6.32 (2H, m), 6.32-6.30 (1H, m), 3.84 (4H, t, J=6.6 Hz), 1.67-1.63(4H, m), 1.27-1.24 (76H, m), 0.88 (6H, t, J=7.0 Hz)

An amount of 294 mg (0.3 mmol) of compound 16 were dissolved in 5 ml ofdichloromethane, and 1 ml of acetyl chloride was added and reacted for 1hour at 45° C. After confirming the completion of the reaction by thinlayer chromatography, vacuum distillation was carried out and thesolvent was distilled, and a crystalline substance (compound 17) wasobtained. The thus obtained crystals were dissolved in 10 ml ofdichloromethane, and 180 mg (1.5 equivalents) of FmoO-Cys(tBu)-OH, and262 μl (5 equivalents) of diisopropylethylamine were added and reactedfor 30 min at 0° C. After confirming the completion of the reaction bythin layer chromatography, 500 μl of diazahicycloundecene were added,and further reacted for 10 minutes. After again confirming thecompletion of the reaction by thin layer chromatography, 100 ml ofacetonitrile was added, and the solution was gradually vacuum filteredand crystals were precipitated, and suction filtration was carried outusing a separatory funnel and a crystalline substance was obtained.

The thus obtained crystalline substance was dissolved in 10 ml ofdichloromethane, and 175 mg (1.5 equivalents) of Fmoc-Phe-OH, 188 μl (4equivalents) of diisopropylcarbodiimide, and 162 mg (4 equivalents) of1-hydroxybenzotriazole were added and reacted for 1 hr at roomtemperature. After confirming the completion of the reaction by thinlayer chromatography, 100 ml of acetonitrile were added, and the solventwas gradually vacuum distilled and crystals were precipitated, andsuction filtration was carried out using a separatory funnel and 371 mgof compound 10 were obtained. The yield was 83%. The thus obtainedcrystalline substance was dissolved in 10 ml of a previously adjusted0.1% trifluoroacetic acid/dichloromethane solution and reacted for 1hour. After confirming the completion of the reaction by thin layerchromatography, 100 ml of acetonitrile were added, and the solution wasgradually vacuum distilled and crystals were precipitated, and suctionfiltration was carried out using a separatory funnel. By vacuumdistillation of the obtained solution, the desired compoundFmoc-Phe-Cys(tBu)-OH (compound 19) was obtained. Further, confirmationof the desired product was carried out in a mass spectrograph.

Compound 17; chloro-3,5-bis(docosyloxy)phenyl-4,4-dichlorophnylmethane

Structural Analysis of Compound 17

¹H-NMR (CDCl₃, 300 MHz) δ 7.36-7.06 (8H, m), 6.45-6.20 (3H, m),4.01-3.59 (4H, m), 1.83-1.49 (4H, m), 1.40-1.10 (76H, m), 0.88 (6H, t,Hz)

Structural Analysis of Compound 19

HRMS m/z (ESI) calculated for [M+H]⁺ 547.2267. found 547.2274

Example 13 Synthesis of Reagent for Organic Synthesis having a TritylGroup

An amount of 1570 mg (2.0 mmol) of 3,5 bis(docosyloxy)methyl benzoicacid was dissolved in 30 ml of tetrahydrofuran, and 9 ml of a solutionof phenylmagnesiumbromide tetrahydrofuran was added and stirring wascarried out for 2 hours at 76° C. After confirming the completion of thereaction by thin layer chromatography, 40 ml of 1 N hydrochloric acidwas added and the reaction was stopped. After this, extraction wascarried out 3 times with 30 ml of hexane, and the extracted organicphase was washed once with 30 ml of 1 N hydrochloric acid, once with asaturated aqueous solution of sodium hydrogen carbonate, and once with asaturated saline solution, and dried with magnesium sulfate. After partof the solution was vacuum distilled, 100 ml of methanol were added tothe solution and crystals precipitated, and suction filtration wascarried out with a separatory funnel, and 1456 mg of compound 20 wereobtained. The yield was 80%. Compound 20;3,5-bis(docosyloxy)phenyl-diphenyl alcohol

Structural Analysis of Compound 20

¹H-NMR (CDCl₃, 300 MHz) δ 7.70-6.80 (10H, m), 6.45-3.38 (2H, m),6.38-6.34 (1H, m), 3.84 (4H, t, J=6.6 Hz), 1.74-1.56 (4H, m), 1.50-1.10(76H, m), 0.88 (6H, t, J=6.6 Hz)

An amount of 1000 mg (1.1 mmol) of compound 20 was dissolved in 30 ml ofdichloromethane, and 234 μl (3.3 mmol) of thionyl chloride was added andreacted for 1 hour at room temperature. After confirming the completionof the reaction by thin layer chromatography, the solvent was vacuumdistilled, and a crystalline substance (compound 21) was obtainedquantitatively. Compound 21;chloro-3,5-bis(docosyloxy)phenyl-diphenylmethane

Structural Analysis of Compound 21

¹H-NMR (CDCl₃, 300 MHz) δ 7.33-7.22 (10H, m), 6.40-6.30 (3H, m), 3.63(4H, t, J=6.6 Hz), 1.80-1.60 (4H, m), 1.50-1.10 (76H, m), 0.88 (6H, t,J=6.6 Hz)

Example 14 Reaction of Reagent for Organic Synthesis Having a TritylGroup and Amino Acid

An amount of 513 mg (3.3 mmol) of H-Ser-OMe was dissolved in 20 ml ofdichloromethane. Then, 1150 μl (6.6 mmol) of diisopropylethylamine wasadded and in addition, the full amount of compound 21 synthesized inExample 13 was added and stirring was carried out for 30 minutes. Afterconfirming the completion of the reaction by thin layer chromatography,100 ml of acetonitrile were added, and the dichloromethane was vacuumdistilled at room temperature. By carrying out suction filtration onthis with a separatory funnel, a crystalline substance (compound 22) wasquantitatively obtained. Compound 22;2-(3,5-bis(docosyloxy)phenyl)-diphenylamino-3-hydroxypropane ethyl ester

Structural Analysis of Compound 22

¹H-NMR (CDCl₃, 300 MHz) δ 7.60-7.10 (10H, m), 6.64-6.60 (2H, m),6.29-6.25 (1H, m), 3.82 (4H, t, J=6.6 Hz), 3.78-3.60 (2H, m), 3.60-3.50(1H, m), 3.32 (3H, s), 1.74-1.56 (4H, m), 1.50-1.10 (76H, m), 0.88 (6H,t, J=6.6 Hz)

INDUSTRIAL APPLICABILITY

The reagent for organic synthesis and the method of organic synthesisreaction of the present invention make it possible to accelerate theresearch and development of pharmaceuticals and the like by compoundlibraries, and in addition contribute to technical innovation in thebiochemical and chemical industries. Because the reagent can beefficiently used and recovered, it provides an innovative technologywhich contributes to the development of “green chemistry”.

1-6. (canceled)
 7. A method for using a reagent shown in the followingChemical Formula (1) in an organic synthesis reaction:

wherein R₁, R₃ and R₅ are hydrogen, and R₂ and R₄ are independentlyselected from the group consisting of alkyl group with a carbon numberof 18 to 30 which may have a substituent group, alkoxyl group with acarbon number of 18 to 30 which may have a substituent group, aryl groupwith a carbon number of 18 to 30 which may have a substituent group,acyl group with a carbon number of 18 to 30 which may have a substituentgroup, thioalkyl group with a carbon number of 18 to 30 which may have asubstituent group, and dialkylamino group with a carbon number of 18 to30 which may have a substituent group, and X represents a reagent activesite shown by the following formulas (A) to (F), (H) to (M), (O), (A′)to (F′), or (H′) to (M′)

wherein, in the formulas (A) to (F), (H) to (M) and (O), Y is an esterbond, ether bond, amide bond, thioester bond, sulfide bond, urea bond,carbamate bond, or carbonate bond, or a alkylene group with a carbonnumber of 1 to 10 which may have one of these bonds, and in formulas (M)and (M′), m and n are each independently 0 or 1, Za is a chlorine atomor a bromine atom, Zb is a hydroxyl group, chlorine atom, or a bromineatom, comprising the following steps: (a) dissolving the reagent in areaction system, (b) reacting the reagent active site X of ChemicalFormula (1) with a target compound, and (c) separating a complex of thereagent and the target compound from the reaction system by reversiblychanging the reagent from a liquid phase state to a solid phase stateaccording to changes in solution composition and/or solutiontemperature.
 8. The method of claim 7, wherein the reagent is used as anucleophilic scavenger, an electrophilic scavenger, a reactionsubstrate, a synthesis building block, a reaction accelerator, acatalysis, a condensation agent, a metal ligand, or a peptide synthesisreagent.
 9. The method of claim 7, wherein said Chemical Formula (1), R₂and R₄ are a docosyloxy group (C₂₂H₄₅O—).
 10. The method of claim 7,wherein the reagent active site X in said Chemical Formula (1) is shownby said formula (M) or (M′).
 11. The method of claim 7, wherein thereagent is shown in the following Chemical Formula 2,


12. A method for using the reagent is shown in the following ChemicalFormula (23) or (23′).

comprising the following steps: (a) dissolving the reagent in a reactionsystem, (b) reacting the reagent active site X of Chemical Formula (1)with a target compound, and (c) separating a complex of the reagent andthe target compound from the reaction system by reversibly changing thereagent from a liquid phase state to a solid phase state according tochanges in solution composition and/or solution temperature.
 13. Themethod of claim 7, wherein the step (c) comprising a means of changingcomposition and/or temperature of a reaction solvent to crystallize thereagent.
 14. The method of claim 7, wherein the means of changingcomposition of a reaction solvent is adding a poor solvent with respectto the reagent to the reaction system, or concentrating the reactionsolvent.
 15. The method of claim 7, wherein the means of changingtemperature of a reaction solvent is cooling the reaction system. 16.The method of claim 7, wherein the step (c) comprising a liquid-liquidextraction method by adding a separation solvent which is immisciblewith the reaction solvent, and partitioning the reagent into theseparation solvent.
 17. The method of claim 7, wherein the organicsynthesis reaction is a peptide synthesis reaction and the targetcompound is an amino acid.
 18. The method of claim 17, furthercomprising an amino acid extension reaction step in which another aminoacid is reacted with the amino acid of the complex.
 19. The method ofclaim 18, further comprising, after the completion of the peptidesynthesis reaction, a step of separating the synthesized peptide fromthe reagent by adding an acid.
 20. The method of claim 7, wherein theseparating step comprises changing the reagent from the liquid phase tothe solid phase by reducing the solution temperature.
 21. The method ofclaim 7, wherein the reaction system comprises a reaction solvent, andthe separating: step comprises reversibly changing the reagent from aliquid phase to a solid phase by adding a second solvent having a highaffinity for the reaction solvent.
 22. The method of claim 7, whereinthe separating step comprises increasing the reagent concentration inthe solution.